Project Summary/Abstract Organisms with regenerative abilities have been informative models for uncovering natural mechanisms by which nervous system damage activates stem or progenitor cells for injury repair. The timing, location, and extent of injuries are not predetermined, requiring the existence of mechanisms that instruct tissue restoration activities that perfectly counter the effects of damage. A key question to understand this process is how cessation of regenerative growth is accomplished. To begin to address this question, it is essential to define the transcriptional and cell signaling systems that negatively regulate adult regenerative neurogenesis. While regenerative tissues have been extensively probed for positive regulators of regeneration, much less is known about factors that act in opposition and whose inhibition could lead to enhanced neural regeneration. In the aims of this grant, this deficit is addressed by leveraging expertise in the planarian system, which uniquely allows access to the biology of complete adult brain regeneration. Uncovering the conserved and fundamental mechanisms used by organisms to limit the extent and rate of tissue regeneration and cell turnover will provide foundational insights into understanding and ultimately treating diseases characterized by an inability to undergo sufficient neural repair.